During the natural transmission of Leishmania, sand flies inoculate low numbers of metacyclic promastigotes, along with saliva, into the skin of the mammalian host. It was previously shown that saliva can enhance the infectivity of Leishmania. Most individuals who live in endemic areas, however, are exposed to saliva from uninfected flies before the bite that transmits infection. We have attempted to establish a model of cutaneous leishmaniasis in the mouse that mimics these natural conditions of infection: low number of metacyclic promastigotes (103), inoculation into the ear dermis, and co-inoculation with salivary lysates from a natural vector, P. papatasi, into naive mice or to mice pre-exposed to saliva. Our studies reveal a dramatic exacerbating effect of saliva on lesion development in the dermal site. The dermal lesions appeared earlier, progressed to a larger size, were more destructive, and contained greater numbers of parasites. Disease exacerbation was associated with the ability of saliva to elicit an early increase (6 hr.) in the frequency of cells producing type 2 cytokines in the epidermis. Furthermore, the exacerbating effect was not seen in IL-4 knockout. The ability of saliva to exacerbate dermal lesions was completely abrogated in mice that had been previously injected with salivary gland lysates. These mice made anti-saliva antibodies that were shown to neutralize the ability of saliva to enhance infection and to elicit type 2 responses in the epidermis. These results introduce the notion that the exposure history of individuals to vector saliva will influence the outcome of infection with Leishmania. There are few reports of successful transmission to experimental animals by bite, and virtually none have explored the host inflammatory and immune response to sand fly initiated infections. A reproducible murine ear model based on the transmission of L. major by bite was established. The model was used to investigate the effect of host presensitization to sand fly saliva via exposure to uninfected sand fly bites on the course of infection. The number of dermal lesions produced was greater, and the progression of lesions, measured by diameter and thickness, was significantly faster in naive mice. Preliminary analyses of the early response in the dermis to the bites of infected flies revealed a dramatic increase in the number of epidermal cells producing type 2 cytokines, especially IL-5, in BALB/c. This response was eliminated in mice pre-exposed to sand fly bites, further supporting a role for these cytokines in the exacerbation of disease by saliva. Despite the importance of L. tropica as the cause of a widely distributed, highly endemic form of cutaneous leishmaniasis in the Old World, no vector studies involving L. tropica have been reported. A laboratory colony of Phlebotomus sergenti, which is the natural vector of L. tropica transmission, was successfully established, and used to reveal a high degree of specificity in vectorial capacity for L. tropica sp. vs. other Leishmania strains. This finding has important epidemiologic considerations.